This invention relates to NMR contrast (MRI) enhancing agents, especially for blood containing portion of the body and in joints, and to their use as such.
The use of NMR imaging as a diagnostic tool is less than 2 decades old. For a discussion of the history of the development of this technology, see Science 83, (1983), July/August Issue, pp. 60-65. For a general explanation of the technology, see Pykett, Ian L., Scientific American, 1982, May, pp. 81-88.
Medically useful NMR images presently are generated from the resonance of hydrogen nuclei provided by water and small, hydrogen-rich molecules in the body fluids and tissues. Differences in concentration, amounts, and source of these hydrogen nuclei in different regions of the body area being examined permits the generation by computer of images of that area. Proposed and established uses of NMR images include detection of tumors and other abnormalities of the brain, breast, kidney and lung, cancers, distinguishing benign from malignant tumors, detection of necrotic tissue and ischemia, diagnosing heart attacks, heart disease, degenerative diseases, strokes, arthritis and a variety of lesions, e.g., of the kidney and other organs, and evaluation of the effect of treatment on known cancerous tumors.
Notwithstanding the great potential of NMR in conjunction with a contrast enhancing agent as a soft tissue imaging technique, there are a variety of situations where current NMR technology generates a less than optimum image. One example is on joints, especially the knee joint. Therefore, there is considerable interest in NMR contrast-enhancing agents which, when present in the area around the joint, enhance the emitted signal by reducing the relaxation time of the blood or joint fluid in the area subjected to the NMR imaging.
NMR imaging agents are, by definition, paramagnetic, i.e., they have an unpaired electron. Polyvalent paramagnetic metal-containing compounds, e.g., organogadolinium compounds, are obvious candidates as NMR contrast enhancing agents but most are too toxic or irritating or present residual heavy metal deposition problems to be viable commercial products for in vivo use in human soft abdominal tissues or joints.
Nitroxides similarly have the theoretical potential for use commercially as in vivo NMR contrast enhancing agents because they meet several of the criteria required for all such products, e.g., prolonged storage stability at varying pH and temperature, feasible methods of preparation, good shelf life, chemical flexibility which permits structural variation to adapt to specific end-use environments, and longer spin relaxation times compared to inorganic paramagnetic ions. However, nitroxides generally are not practical for such use because they are rapidly enzymatically reduced in tissues to products which do not enhance the NMR signal. See "Pharmacokinetics of Nitroxide NMR Contrast Agents," Griffeth, et al., Invest. Radiol. 19:553-562 (1984), of which I am coauthor. Brasch, et al., in Radiology 147:773-779 (1983), report the successful enhancement of an NMR image with "TES", a piperidine mononitroxide stable free radical. Although that compound is stated by the authors to have an in vivo half life of 38 minutes, the dosage employed by them to achieve a substantial increase in intensity of signal from the renal parenchyma was huge, viz., 0.5 g/kg body weight by intravenous injection. Such a high dose suggests that the authors compensated for the rapid enzymatic reduction of the nitroxide by the use of such a massive dose of the nitroxide that it overwhelmed reductases in the tissue under study. I have found that unless the enzyme system is overwhelmed in this manner, the in vivo reduction of virtually all nitroxides is virtually instantaneous. Needless to say, such a procedure is contraindicated for human use. Because of the relatively low electrochemical potential, viz., about 300 mV, which is characteristic of all nitroxides having an isolated nitroxide group, the rapid enzymatic reduction and, accordingly, their limited half-life at acceptably low blood levels, have rendered nitroxides as a class poor candidates as commercially useful medical NMR image enhancing agents.
U.S. Pat. No. 3,704,235 is concerned with the preparation of tropane nitroxides. These compounds are quite toxic because they are reduced by enzymes such as FAD-containing monooxygenase to give superoxide. They are also too unstable to have a useful half-life in vivo.
U.S. Pat. No. 3,716,335 relates to the use of nitroxides as sensors of certain electron transfer reactions and is not related to the use of nitroxides as NMR contrast enhancing agents.
U.S. Pat. No. 3,702,831 relates to the use of nitroxides as magnetometer to monitor magnetic fields. This is only remotely related in that the magnetic field set-up by the free radical interacts with an applied field. Thus, the nitroxide becomes a marker, a probe. The compound used, viz., di-tert-butylnitroxide is rapidly eliminated in vivo.
U.S. Pat. No. 4,099,918 describes the synthesis of pyrrolidinoxyl as probes to study biological systems. There is no mention in this patent of NMR enhancing activity. Nitroxides have been used for years as probes of membrane structure.
Published European Patent Appln. 84 10 8900.6 discloses as stable NMR image enhancing agents nitroxides of the formula ##STR2## wherein B is a protein, sugar or lipid residue or --NR.sub.1 R.sub.2.
Chem. Abstr. 88:134654s discloses 2,2,5,5-tetramethylpyrrolinyl-1-oxyl-saccharides.
Chem. Abstr. 90:137610b discloses a nitroxide of the formula ##STR3## wherein R is --COOH or --CONH--C(CH.sub.3).sub.2 --OH.
French Application No. 73 23978 (Publication No. 2,235,103) discloses nitroxides of the formula ##STR4## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are alkyl.
Golding, B. T. et al, Synthesis, 1975, No. 7, 462-433, discloses nitroxides of the formulae ##STR5## wherein X is OH, Cl, OC.sub.2 H.sub.5, piperidino, anilino, benzylamino, hydroxyethylamino or carbethoxymethylamino.
I have found that although in general nitroxides have too short a half-life in blood to be useful as vascular NMR contrast enhancing agents, surprisingly within these classifiable are classes of nitroxides which are useful as vascular NMR contrast enhancing agents, as well as contrast enhancing agents for joints such as the knee.